The signal transducer and activator of transcription (STAT) proteins are considered a family of transcriptional factors that are activated in response to growth factors and cytokines and promote cell proliferation and survival (Yu, et al. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol. 2007; 7, 1:41-51). Extracellular signals can activate Janus kinases (JAKs) and receptor tyrosine kinases that in turn activate STATs by phosphorylating a critical tyrosine residue in the active site. A promising location for STAT3 inhibition could be the Src Homology 2 (SH2) domain of STAT3, inhibiting the STAT3 molecule by directly preventing phosphorylation of STAT3, or preventing active phospho-STAT3 homodimer formation. Two phosphorylated STAT monomers are believed to form a homodimer that translocates to the nucleus to bind specific DNA-response elements in the promoters of target genes and induce gene expression (Yu, et al. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science. 1995; 269, 5220:81-83).
In normal cells, the activation of STAT proteins is very transient and strictly regulated; however, evidence suggests that some STATs may play a key role in oncogenesis (Yu H, Jove R. The STATs of cancer—new molecular targets come of age. Nat Rev Cancer. 2004; 4, 2:97-105). Specifically, STAT3 has been found to be constitutively active in leukemia, lymphoma, breast, and lung and most recently in malignant gliomas (Brantley E, Benveniste E. Signal transducer and activator of transcription-3: a molecular hub for signaling pathways in gliomas. Mol Cancer Res. 2008; 6, 5:675-684; Iwamaru, et al. A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo. Oncogene. 2007; 26, 17:2435-2444; Hussain, et al. A novel small molecule inhibitor of signal transducers and activators of transcription 3 reverses immune tolerance in malignant glioma patients. Cancer Res. 2007; 67, 20:9630-9636). Furthermore, inhibition of STAT3 signaling leads to inhibition of cancer cell growth and leads to the induction of apoptosis. STAT3 is believed to mediate tumor-induced immunosuppression at many levels. Activation of STAT3 also mediates propagation of tumor-promoting inflammation and suppression of anti-tumor immunity. Thus, blocking STAT3 activation holds promise for improving cancer treatment by modulating immune responses. (Yu et al., STATs in cancer inflammation and immunity; a leading role for STAT3. Nat Rev Cancer. 2009; 9:798-809)
STAT3 inhibitors exhibit potential as anticancer drugs. Some examples include WP1066, STA21, LLL12, and S31-201. Of these, only a few show good activity in terms of inhibiting STAT3 functions and inhibiting tumor growth in vitro and in vivo. WP1066 has shown more consistent in vitro and in vivo activity in malignant glioma cells. STA-21, the first direct small molecule STAT3 inhibitor, is a natural product with a complex structure that can be synthetically difficult to synthesize. LLL-12, a simplified version of STA-21, shows good inhibition of STAT3 activity both in-vitro and in-vivo and may be considered a potent inhibitor. However, LLL-12 is hard to synthesize with a reported yield of 2.5%; it can also be easily oxidized and therefore not stable, and it is difficult to generate analogs because of the chemistry involved. Various peptides/peptidomimetic compounds have been developed based on the phosphotyrosine sequence of STAT3 or gp130 and show potent STAT3 inhibitory activity. However, significant limitations exist to developing these compounds into drugs due to their peptide nature. There appears to be no evidence that a suitable STAT3 inhibitor is near clinical development.
It is for these shortcomings that new or improved agents which inhibit STAT3, such as pyrazole derivatives, are continually needed for developing new and more effective pharmaceuticals that are aimed at suppression of oncogenesis. The compounds of the invention, as well as their compositions and methods described herein are directed toward these needs and other ends.